Endogenous HMGB1 contributes to ischemia-reperfusion-induced myocardial apoptosis by potentiating the effect of TNF-α/JNK

Abstract

High-mobility group box 1 (HMGB1) is a nuclear protein that has been implicated in the myocardial inflammation and injury induced by ischemia-reperfusion (I/R). The purpose of the present study was to assess the role of HMGB1 in myocardial apoptosis induced by I/R. In vivo, myocardial I/R induced an increase in myocardial HMGB1 expression and apoptosis. Inhibition of HMGB1 (A-box) ameliorated the I/R-induced myocardial apoptosis. In vitro, isolated cardiac myocytes were challenged with anoxia-reoxygenation (A/R; in vitro correlate to I/R). A/R-challenged myocytes also generated HMGB1 and underwent apoptosis. Inhibition of HMGB1 attenuated the A/R-induced myocyte apoptosis. Exogenous HMGB1 had no effect on myocyte apoptosis. However, inhibition of HMGB1 attenuated myocyte TNF-α production after the A/R was challenged; surprisingly, HMGB1 itself did not induce myocyte TNF-α production. Exogenous TNF-α induced a moderate proapoptotic effect on the myocytes, an effect substantially potentiated by coadministration of HMGB1. It is generally accepted that apoptosis induced by TNF-α is regulated by the balance of activation of c-Jun NH(2)-terminal kinase (JNK) and NF-κB. Indeed, in the present study, TNF-α increased the phosphorylation status of JNK and p65, a subunit of NF-κB; HMGB1 greatly potentiated TNF-α-induced JNK phosphorylation. Furthermore, inhibition of JNK (SP-600125) prevented the myocyte apoptosis induced by a TNF-α/HMGB1 cocktail. Finally, A/R increased HMGB1 production in both wild-type and toll-like receptor 4-deficient myocytes; however, deficiency in toll-like receptor 4 diminished A/R-induced myocyte apoptosis, TNF-α, and JNK activation. Our results indicate that myocyte-derived HMGB1 and TNF-α work in concert to promote I/R-induced myocardial apoptosis through JNK activation.

Glycyrrhizin protects rat heart against ischemia-reperfusion injury through blockade of HMGB1-dependent phospho-JNK/Bax pathway

“…Hence, it is possible that upon release, HMGB1 directly or indirectly activates phospho-JNK pathway, which is supported by our results obtained due to the administration of rHMGB1 in this study. Moreover, recent studies have demonstrated that HMGB1 triggered a substantial potentiation of TNF-α-induced JNK phosphorylation and that inhibition of JNK (SP600125) prevented the myocyte apoptosis induced by a TNF-α/HMGB1 cocktail [29] ; these findings support our hypotheses.…”

“…Because the anti-apoptotic effect of GL has been linked to the inhibition of HMGB1 and caspase-dependent cytochrome c release in vivo and ex vivo, the question that remains now concerns how GL regulates the BAX translocation and caspase-dependent cytochrome c release via the inhibition of HMGB1. The exact answer is currently unknown, but we speculate that GL may modulate the activity of a particular kinase, which contributes to BAX translocation and is involved in I/R-induced HMGB1-dependent apoptosis based on the following evidence: (1) Glycyrrhizin can alleviate HMGB1-induced hepatocyte apoptosis by inhibiting the p38-dependent mitochondrial pathway in Huh-BAT cells [27] ; (2) the JNK signaling pathway mediates Bax translocation and subsequent neuronal apoptosis through interaction with Bim after transient focal cerebral ischemia [20] ; (3) myocyte-derived HMGB1 and TNF-α work together to promote I/R-induced myocardial apoptosis through JNK activation [29] ; (4) blockade of HMGB1 using HMGB1 box A, another HMGB1 inhibitor, effectively decreased the phosphorylation of ERK1/2 and JNK, and finally reduced I/R-induced apoptosis injury [16] . The mitochondria-dependent apoptosis pathway is tightly regulated by the MAP kinase family, and JNK, ERK1/2, and p38 members of this family have been demonstrated to be activated in I/R injury [12,13] .…”

Extracellular high‐mobility group box 1 mediates pressure overload‐induced cardiac hypertrophy and heart failure

“…There exist growing recognition and experimental evidence to support that HMGB1 plays a pivotal role not only in the diseases such as sepsis, autoimmune disease, acute hepatic necrosis, acute lung injury 25, 26, 27, 28 but also in various heart diseases, including myocardial infarction and ischaemia‐reperfusion injury, however, with no consensus on the function of HMGB1 on the pathogenesis of the diseases 9, 16, 29, 30, 31, 32, 33, 34.…”

Cathepsin B deficiency attenuates cardiac remodeling in response to pressure overload via TNF-α/ASK1/JNK pathway

“…Internalized TNF-R2 via ASK1 can form a complex with AIP1, leading to JNK activation (15). Activated JNK signaling controls the release of cytochrome c and induces the apoptotic (38) and cardiac hypertrophic (36) programs. In our study, we found that CTSB deficiency blocked the pressure overload induced the release of TNF-␣ and activation of ASK1, JNK, and c-Jun (the proximal downstream product of JNK) and enhanced the release of cytochrome c. The JNK inhibitor SP600125 eliminated the activated JNK signaling provoked by TNF-␣ in CTSB overexpressed cardiomyocytes in response to ANG II.…”